Heparin-based compositions and methods for the inhibition of metastasis

ABSTRACT

The invention provides the use in combination of a heparin containing composition that has anticoagulant activity when used alone, such as an unfractionated heparin or low molecular weight heparin, in combination with an inhibitor of the anticoagulation activity/effect or effect of heparin, for the inhibition of metastasis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/564,967 filed Dec. 9, 2014 (now U.S. Pat. No. 9,173,889) which is adivision of U.S. application Ser. No. 13/477,012 filed May 21, 2012 (nowU.S. Pat. No. 8,912,167) which claims the benefit of U.S. provisionalpatent application Ser. Nos. 61/511,244 filed Jul. 25, 2011 and61/488,068 filed May 19, 2011, each of which is incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to field of pharmaceutical prevention andtreatment of metastasis.

BACKGROUND

Heparin is a mixture of glycosaminoglycan chains generally ranging inmolecular weight from approximately 3,000 to 30,000 Daltons. Bothunfractionated and low molecular weight heparins are utilized inmedicine for their anticoagulant activity. Many studies have also nowdocumented that unfractionated and low molecular weight heparins inhibitcancer cell metastasis. However, the use of heparins in the preventionor treatment of cancer metastasis is severely limited by theanticoagulant activity.

What is needed and provided by the present invention are compositionsand related methods that permit the anti-metastatic activity of heparinto be used in the treatment of cancer by reducing or eliminating theanticoagulant activity of heparin.

SUMMARY OF THE INVENTION

One embodiment of the invention provides a pharmaceutical compositionfor the inhibition of metastasis that includes:

-   -   an anti-metastatic heparin preparation having anti-coagulant        activity in the absence of an inhibitor thereof; and    -   an inhibitor of the anti-coagulation activity of heparin or a        pharmaceutically-acceptable salt thereof.

The composition may be dry or friable. The composition may furthercomprise water and be a liquid. If the composition is dry, it may bereconstitutable with water or aqueous solution to a liquid form suitablefor intravenous administration or injection such as subcutaneous orbolus injection in a mammal such as a human. The heparin preparation maybe present in the composition in an amount effective to inhibitmetastasis and the inhibitor of the anti-coagulation activity of heparinin the composition may be present in an amount effective to at leastpartially inhibit, such as at least substantially inhibit, theanti-coagulation activity of the heparin preparation in the composition.At least a portion of the inhibitor of the anti-coagulation activity ofheparin or a pharmaceutically-acceptable salt thereof in the compositionmay be bound to the heparin of the heparin preparation in thecomposition.

A related embodiment of the invention provides a method for preparing anaqueous pharmaceutical composition for the inhibition of metastasis in amammal that includes mixing

-   -   an anti-metastatic heparin preparation having anti-coagulant        activity in the absence of an inhibitor thereof;    -   an inhibitor of the anti-coagulation activity of heparin or a        pharmaceutically-acceptable salt thereof; and    -   water or an aqueous solution to obtain the aqueous        pharmaceutical composition. The inhibitor may be a        heparin-binding compound and the method may optionally include a        further step of removing inhibitor that remains unbound to the        heparin, for example, by filtering.

Another embodiment of the invention provides a pharmaceutical kit forthe inhibition of metastasis that includes:

-   -   an anti-metastatic heparin preparation having anti-coagulant        activity in the absence of an inhibitor thereof; and    -   an inhibitor of the anti-coagulation activity of or a        pharmaceutically-acceptable salt thereof,        wherein, the heparin preparation is not mixed with the inhibitor        of the anti-coagulation activity of heparin in the kit. The        components may, for example, be provided in separate vials or        other containers. Each of said components may be in dry form in        the kit. The heparin preparation in the kit may be provided in        an amount effective to inhibit metastasis and the inhibitor of        the anti-coagulation activity of heparin in the kit may be        provided in an amount effective to at least partially inhibit,        such as at least substantially inhibit, the anti-coagulation        activity of the heparin preparation in the kit.

A further embodiment of the invention provides a method for inhibitingmetastasis in a mammal, that includes the step of:

-   -   administering to a mammalian subject, such as a human, in need        of inhibition of metastasis, an effective amount of a        pharmaceutical composition that includes (i) an anti-metastatic        heparin preparation having anti-coagulant activity in the        absence of an inhibitor thereof, and (ii) an inhibitor of the        anti-coagulation effect of heparin or a        pharmaceutically-acceptable salt thereof. The mammalian subject        may not be in need of treatment for pathological coagulation or        not be in need of anti-coagulation generally. The subject may        have a cancer that is susceptible to or exhibiting metastasis.        The composition administered may contain an amount of the        heparin preparation effective to inhibit metastasis and an        amount of the inhibitor of the anti-coagulation activity of        heparin effective to at least partially, for example, at least        substantially, inhibit the anti-coagulation activity of the        heparin preparation (while both components are in the body).        Administration may, for example, include intravenous        administration or injection, such as subcutaneous or        intramuscular bolus injection.

Another embodiment of the invention provides a method for inhibitingmetastasis in a mammal that includes the step of:

-   -   administering, for example co-administering, to a mammalian        subject in need of inhibition of metastasis,        -   (i) an anti-metastatic heparin preparation having            anti-coagulant activity in the absence of an inhibitor            thereof; and        -   (ii) an inhibitor of the anti-coagulation effect of heparin            or a pharmaceutically-acceptable salt thereof,    -   such that the presence of the heparin preparation and the        inhibitor in the mammalian subject are temporally overlapping.        The mammalian subject may not be in need of treatment for        pathological coagulation or not be in need of anti-coagulation        generally. The heparin preparation may be administered in an        amount effective to inhibit metastasis and the inhibitor of the        anti-coagulation activity of heparin may be administered in an        amount effective to at least partially, for example, at least        substantially, inhibit the anti-coagulation activity of the        heparin preparation (while both components are in the body). The        subject may have a cancer that is susceptible to or exhibiting        metastasis. Administration may, for example, include intravenous        administration or injection, such as subcutaneous or        intramuscular bolus injection.

A further embodiment of the invention provides the use in combination ofan anti-metastatic heparin preparation having anti-coagulant activity inthe absence of an inhibitor thereof and an inhibitor of theanti-coagulation activity of heparin for the inhibition of metastasis ina mammalian subject such as a human.

Another embodiment of the invention provides the use of a pharmaceuticalcomposition including an anti-metastatic heparin preparation havinganti-coagulant activity in the absence of an inhibitor thereof and aninhibitor of the anti-coagulation activity of heparin, for theinhibition of metastasis in a mammalian subject such as a human.

A further embodiment of the invention provides the use of ananti-metastatic heparin preparation having anti-coagulant activity inthe absence of an inhibitor thereof and an inhibitor of theanti-coagulation activity of heparin for the preparation of a medicamentfor the inhibition of metastasis in a mammalian subject such as a human.

The heparin preparation in any of the aforementioned embodiments mayinclude or be an unfractionated heparin preparation or a low molecularweight heparin preparation. The low molecular weight heparin preparationmay, for example, include or be a heparin preparation selected from thegroup consisting of Tinzaparin, Reviparin and Enoxaparin.

The inhibitor of the anti-coagulation activity of heparin or apharmaceutically-acceptable salt thereof may, for example, be any of theanti-heparin compounds disclosed herein including the specific compoundsand compounds of the formulas disclosed herein (or theirpharmaceutically acceptable salts). The inhibitor may, for example, bean inhibitor that binds heparin, such as binding an antithrombin bindingsite of heparin. In any of the aforementioned embodiments, the inhibitorof the anti-coagulation activity of heparin may include or betetra-[5-(L)-lysyl-amino-O-methylsalicylamide] or apharmaceutically-acceptable salt thereof.

Other objects and advantages of the invention will become apparent fromthe following description.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides the use in combination of a heparin-containingcomposition that has anticoagulant activity when used alone, such as anunfractionated heparin or low molecular weight heparin, in combinationwith an inhibitor of the anticoagulation activity/effect or effect ofheparin (or procoagulant generally), for the inhibition of metastasis.The heparin and inhibitor of the anticoagulation activity/effect ofheparin may be provided in the same pharmaceutical composition or may beprovided separately, but administered to the patient such that theireffect is overlapping in the patient. The heparin component of thecombination treatment inhibits metastasis while the inhibitor of theanticoagulation activity/effect of heparin ensures that the patient whois not in need of anticoagulation and/or may be harmed byanticoagulation, will at least partially, for example at leastsubstantially, not have coagulation inhibited by the administeredheparin.

The patient may, for example, be a patient diagnosed or previouslydiagnosed with a cancer that is known to metastasize (susceptible tometastasis) or a patient suspected of having or developing such acancer. The amount of the heparin administered to the patient iseffective to inhibit metastasis and the amount of the inhibitor of theanticoagulation activity/effect of heparin administered to the patientis effective to at least partially, for example at least substantially,inhibit the anticoagulation activity/effect of the administered heparin,for example, by at least 40%, by at least 50%, by at least 60%, by atleast 70%, by at least 75%, by at least 80%, by at least 85% by at least90%, or by at least 95%. The patient may be a mammal, such as a humanpatient. The primary cancer type may, for example, be lung cancer,NSCLC, breast cancer, ovarian cancer, prostate cancer, testicularcancer, pancreatic cancer, melanoma, sarcoma, cervical cancer, kidney(renal) cancer, gastric cancer, colon cancer, bladder cancer, mouthcancer, or throat cancer. The invention also provides methods fortreating cancers with the compositions of the invention that are notconventionally thought of as metastatic or at risk of metastases butwhose growth and spreading at one or more stages of disease may utilizesome of the same biological interactions found in metastasis. Suchcancers include myeloma such as multiple myeloma, leukemia, lymphoma,brain cancer and esophageal cancer.

Without limitation, various embodiments of the invention include:

1. A pharmaceutical composition for the inhibition of metastasis,including: a heparin preparation; and an inhibitor of theanti-coagulation effect of heparin.

The composition may be a friable and/or dry admixture of the heparinpreparation and the inhibitor of the anti-coagulation effect of heparin,which can be reconstituted with water or aqueous solution such as salinefor intravenous administration or injection such as subcutaneousinjection, to a mammalian patient/subject such as a human.Pharmaceutically acceptable excipients, such as but not limited to oneor more carriers, may also be included in the composition. Thecomposition may be a liquid preparation. Thus, it may further includewater or aqueous solution in which the heparin preparation and inhibitorof the anti-coagulation effect of heparin are dissolved, suspendedand/or dispersed. The liquid composition may be obtained by a method ofreconstitution including a step of mixing the friable or dry mixture ofthe heparin preparation and inhibitor of the anti-coagulation effect ofheparin with water such as with an aqueous solution such as saline.Alternatively, the liquid composition for administration may be preparedby sequentially mixing each the heparin preparation and inhibitor of theanti-coagulation effect of heparin and the water or aqueous in anymanner, such as but not limited to adding one of the heparin preparationand inhibitor of the anti-coagulation effect of heparin to the water oraqueous solution and then the other component.

The inhibitor of the anti-coagulation effect of heparin may, forexample, be a heparin-binding compound, such as one binding theantithrombin binding site of heparin and/or structurally mimicking theheparin binding site of antithrombin. At least a substantial quantity,such as at least 50%, at least 60%, at least 70%, at least 80%, at least90%, at least 95% and at least 98% of the inhibitor of theanti-coagulation effect of heparin in the composition (dry or liquid)may, for example, be bound to the heparin in the composition, such as tothe antithrombin site of the heparin. To manufacture a “dry” or friablecomposition in which the heparin and the heparin binding inhibitor areprebound, the components can be mixed together in water or an aqueoussolution (for example, around a neutral pH) to permit such binding andthen dried such as by lyophilization. Those skilled in the art willrecognized that such a dry composition may still include some water anduse of the term “dry” herein is not intended to suggest that no watermolecules are present in a dry composition. The heparin and heparinbinding inhibitor may also simply be admixed in a dry or friablecomposition so that the binding of the components does not substantiallyoccur until they are mixed with water or aqueous solution.

2. The composition of embodiment 1, wherein the heparin preparation ispresent in an amount effective to inhibit metastasis and the inhibitorof the anti-coagulation activity of heparin is present in an amounteffect to at least partially inhibit the anti-coagulation activity ofthe heparin preparation.

3. The composition of any one of the preceding embodiments, furtherincluding at least one pharmaceutically acceptable excipient.

4. The composition of any one of the preceding embodiments, wherein theheparin preparation is unfractionated heparin.

5. The composition of any one of the preceding embodiments, wherein theheparin preparation is a low molecular weight heparin.

6. The composition of embodiment 5, wherein the low molecular weightheparin is Tinzaparin, Reviparin, or Enoxaparin.

7. The composition of any one preceding embodiments wherein theinhibitor of the anti-coagulation effect of heparin includes a compoundor a pharmaceutically-acceptable salt thereof, the compound beingselected from the group consisting of: PMX-60056(tetra-[5-(L)-lysyl-amino-O-methylsalicylamide], Polymedix; Kuziej etal., Clin Appl Thromb Hemost, 2010 August; 16(4):377-86); PMX-60102(Polymedix); PMX-60126 (Polymedix); PMX-60138 (Polymedix); PMX-60100(Polymedix); a salicylamide derivative; a compound disclosed in US Pub.No. 2009/0239811; protamine; a derivative of protamine; a peptideinhibitor of the anticoagulant activity of heparin such as one of thosedisclosed in Schick et al., Thromb Haemost, 2001 March 85(3):482-487; apeptide inhibitor disclosed in U.S. Pat. No. 6,855,801 or 7,259,140; andan fXa protein derivative such as one disclosed in US Pub. No.2010/0125052.

8. A pharmaceutical kit for the inhibition of metastasis, including: aheparin preparation; and an inhibitor of the anti-coagulation effect ofheparin.

9. The kit of embodiment 8, wherein the heparin preparation is providedin an amount effective to inhibit metastasis and the inhibitor of theanti-coagulation activity of heparin is provided in an amount effect toat least partially inhibit the anti-coagulation activity of the heparinpreparation.

10. The kit of embodiment 8 or 9, wherein at least one of the heparinpreparation and the inhibitor is provided mixed with at least onepharmaceutically acceptable excipient.

11. The kit of any one of embodiments 8-10, wherein the heparinpreparation is an unfractionated heparin.

12. The kit of any one of embodiments 8-10, wherein the heparinpreparation is a low molecular weight heparin.

13. The kit of embodiment 12, wherein the low molecular weight heparinis Tinzaparin, Reviparin, or Enoxaparin.

14. The kit of any one preceding embodiments wherein the inhibitor ofthe anti-coagulation effect of heparin includes a compound or apharmaceutically-acceptable salt thereof, the compound being selectedfrom the group consisting of: PMX-60056(tetra-[5-(L)-lysyl-amino-O-methylsalicylamide], Polymedix; Kuziej etal., Clin Appl Thromb Hemost, 2010 August; 16(4):377-86); PMX-60102(Polymedix); PMX-60126 (Polymedix); PMX-60138 (Polymedix); PMX-60100(Polymedix); a salicylamide derivative; a compound disclosed in US Pub.No. 2009/0239811; protamine; a derivative of protamine; a peptideinhibitor of the anticoagulant activity of heparin such as one of thosedisclosed in Schick et al., Thromb Haemost, 2001 March 85(3):482-487; apeptide inhibitor disclosed in U.S. Pat. No. 6,855,801 or 7,259,140; andan fXa protein derivative such as one disclosed in US Pub. No.2010/0125052.

15. A method for inhibiting metastasis in a mammal, including the stepof:

-   -   administering to a mammalian subject in need thereof, an        effective amount of a pharmaceutical composition according to        any one of embodiments 1-7.

The mammalian subject may be a non-human mammal or a human. Themammalian subject, such as a human, may be in need of inhibition orprevention of metastasis and not in need of anti-coagulation such as notin need of the anti-coagulation effect of heparin. Thus, the mammaliansubject may be one that is not suffering from pathological coagulationactivity. The mammalian subject, such as a human, may have or besuspected of having a cancer that is known to metastasize (susceptibleto metastasizing) or is metastasizing, such as those described herein.

16. The method of embodiment 15, wherein the mammalian subject is ahuman patient.

17. A method for inhibiting metastasis in a mammal, including the stepof:

-   -   administering to a mammalian subject in need thereof,        -   (i) a heparin preparation; and        -   (ii) an inhibitor of the anti-coagulation effect of heparin,            such that the presence of the heparin preparation and the            inhibitor in the mammalian subject are temporally            overlapping.

The mammalian subject may be a non-human mammal or a human. Themammalian subject, such as a human, may be in need of inhibition orprevention of metastasis and not in need of anti-coagulation such as notin need of the anti-coagulation effect of heparin. Thus, the mammaliansubject may be one that is not suffering from pathological coagulationactivity. The mammalian subject, such as a human, may have or besuspected of having a cancer that is known to metastasize (susceptibleto metastasizing) or is metastasizing, such as those described herein.

18. The method of embodiment 17, wherein the heparin preparation and theinhibitor of the anti-coagulation activity of heparin areco-administered.

19. The method of embodiment 17 or 18, wherein the heparin preparationis administered in an amount effective to inhibit metastasis and theinhibitor of the anti-coagulation activity of heparin is administered inan amount effect to at least partially inhibit the anti-coagulationactivity (or effect) of the heparin preparation.

20. The method of any one of embodiment 17 or 18, wherein the heparinpreparation is an unfractionated heparin.

21. The method of any one of embodiments 17-19, wherein the heparinpreparation is a low molecular weight heparin.

22. The method of embodiment 21, wherein the low molecular weightheparin is Tinzaparin, Reviparin, or Enoxaparin.

23. The method of any one of embodiments 17-22, wherein the inhibitor ofthe anti-coagulation effect of heparin is a compound or apharmaceutically-acceptable salt thereof, the compound being selectedfrom the group consisting of: PMX-60056(tetra-[5-(L)-lysyl-amino-O-methylsalicylamide], Polymedix; Kuziej etal., Clin Appl Thromb Hemost, 2010 August; 16(4):377-86); PMX-60102(Polymedix); PMX-60126 (Polymedix); PMX-60138 (Polymedix); PMX-60100(Polymedix); a salicylamide derivative; a compound disclosed in US Pub.No. 2009/0239811; protamine; a derivative of protamine; a peptideinhibitor of the anticoagulant activity of heparin such as one of thosedisclosed in Schick et al., Thromb Haemost, 2001 March 85(3):482-487; apeptide inhibitor disclosed in U.S. Pat. No. 6,855,801 or 7,259,140; andan fXa protein derivative such as one disclosed in U.S. Pub. No.2010/0125052.

24. Use in combination of a heparin preparation and an inhibitor of theanti-coagulation activity of heparin for the inhibition of metastasis ina mammalian subject.

25. The use of embodiment 24, wherein the heparin preparation is anunfractionated heparin.

26. The use of embodiment 25, wherein the heparin preparation is a lowmolecular weight heparin.

27. The use of embodiment 26, wherein the low molecular weight heparinis Tinzaparin, Reviparin, or Enoxaparin.

28. The use of any one of embodiments 24-27, wherein the inhibitor ofthe anti-coagulation effect of heparin is a compound or apharmaceutically-acceptable salt thereof, the compound being selectedfrom the group consisting of: PMX-60056(tetra-[5-(L)-lysyl-amino-O-methylsalicylamide], Polymedix; Kuziej etal., Clin Appl Thromb Hemost, 2010 August; 16(4):377-86); PMX-60102(Polymedix); PMX-60126 (Polymedix); PMX-60138 (Polymedix); PMX-60100(Polymedix); a salicylamide derivative; a compound disclosed in U.S.Pub. No. 2009/0239811; protamine; a derivative of protamine; a peptideinhibitor of the anticoagulant activity of heparin such as one of thosedisclosed in Schick et al., Thromb Haemost, 2001 March 85(3):482-487; apeptide inhibitor disclosed in U.S. Pat. No. 6,855,801 or 7,259,140; andan fXa protein derivative such as one disclosed in US Pub. No.2010/0125052.

29. Use of a pharmaceutical composition according to any one ofembodiments 1-7 for the inhibition of metastasis in a mammalian subjectsuch as a non-human mammal or a human.

30. Use of a heparin preparation and an inhibitor of theanti-coagulation activity of heparin for the preparation of a medicamentfor the inhibition of metastasis in a mammalian subject such as anon-human mammal or a human.

31. The use of embodiment 30 wherein the heparin preparation is anunfractionated heparin.

32. The use of embodiment 30, wherein the heparin preparation is a lowmolecular weight heparin.

33. The use of embodiment 32, wherein the low molecular weight heparinis Tinzaparin, Reviparin, or Enoxaparin.

34. The use of any one of embodiments 30-33, wherein the inhibitor ofthe anti-coagulation effect of heparin is a compound or apharmaceutically-acceptable salt thereof, the compound being selectedfrom the group consisting of: PMX-60056(tetra-[5-(L)-lysyl-amino-O-methylsalicylamide], Polymedix; Kuziej etal., Clin Appl Thromb Hemost, 2010 August; 16(4):377-86); PMX-60102(Polymedix); PMX-60126 (Polymedix); PMX-60138 (Polymedix); PMX-60100(Polymedix); a salicylamide derivative; a compound disclosed in U.S.Pub. No. 2009/0239811; protamine; a derivative of protamine; a peptideinhibitor of the anticoagulant activity of heparin such as one of thosedisclosed in Schick et al., Thromb Haemost, 2001 March 85(3):482-487; apeptide inhibitor disclosed in U.S. Pat. No. 6,855,801 or 7,259,140; andan fXa protein derivative such as one disclosed in U.S. Pub. No.2010/0125052.

35. Any one of the preceding embodiments, wherein the inhibitor of theanti-coagulation effect of heparin is a heparin-binding compound, suchas one binding the antithrombin binding site of heparin.

36. Any one of the preceding embodiments, wherein the inhibitor of theanti-coagulation effect of heparin is an anti-heparin compound of aformula disclosed in U.S. Publication No. 2011/0178104 A1 (U.S.application Ser. No. 12/984,634) or a specific compound disclosedtherein, or a pharmaceutically acceptable salt of the compound(s).

37. Any one of the preceding embodiments, wherein the inhibitor of theanti-coagulation effect of heparin istetra-[5-(L)-lysyl-amino-O-methylsalicylamide] (PMX-60056) or apharmaceutically acceptable salt thereof.

A further embodiment of the invention provides a method for treating acancer susceptible to metastasis in a mammal, that includes the step of:

-   -   administering to a mammalian subject, such as a human,        having/diagnosed with a cancer susceptible to metastasis (such        as those described herein), for example, not yet or already        metastasizing, an effective amount of a pharmaceutical        composition that includes (i) an anti-metastatic heparin        preparation having anti-coagulant activity in the absence of an        inhibitor thereof, and (ii) an inhibitor of the anti-coagulation        effect of heparin or a pharmaceutically-acceptable salt thereof,        such as any of those described herein. The method can at least        partially inhibit metastasis. The composition administered may        contain an amount of the heparin preparation effective to        inhibit metastasis and an amount of the inhibitor of the        anti-coagulation activity of heparin effective to at least        partially, for example, at least substantially, inhibit the        anti-coagulation activity of the heparin preparation (while both        components are in the body).

A related embodiment of the invention provides a method for treating acancer susceptible to metastasis in a mammal such as a human thatincludes the step of:

-   -   administering, for example co-administering, to a mammalian        subject, such as a human, having/diagnosed with a cancer        susceptible to metastasis (such as those described herein), for        example, not yet or already metastasizing,    -   (i) an anti-metastatic heparin preparation having anti-coagulant        activity in the absence of an inhibitor thereof; and    -   (ii) an inhibitor of the anti-coagulation effect of heparin or a        pharmaceutically-acceptable salt thereof, such as any of those        described herein    -   such that the presence of the heparin preparation and the        inhibitor in the mammalian subject are temporally overlapping.        The method can at least partially inhibit metastasis. The        heparin preparation may be administered in an amount effective        to inhibit metastasis and the inhibitor of the anti-coagulation        activity of heparin may be administered in an amount effective        to at least partially, for example, at least substantially,        inhibit the anti-coagulation activity of the heparin preparation        (while both components are in the body.)

The mammalian subject in the aforementioned methods for treating cancermay not be in need of treatment for pathological coagulation or not bein need of anti-coagulation generally. Administration may, for example,include intravenous administration or injection, such as subcutaneous orintramuscular bolus injection. Administration may, for example, beginbefore a patient undergoes surgery and/or radiation to resect or treatthe cancer or immediately after the patient undergoes such surgery orradiation. Administration may begin before such surgery or radiation andcontinue after such surgery or radiation. Administration may, forexample, begin before, during or after (such as immediately orproximally after) a patient undergoes cytotoxic chemotherapy for thecancer. Administration may begin before such cytotoxic chemotherapybegins and continue after the chemotherapy. Administration may beconcurrent with cytotoxic chemotherapy. Each of the methods for treatingcancer may further include administering at least one anticancerpharmaceutical compound, such as but not limited to a cytotoxic agent ortherapeutic antibody or soluble receptor, that is not a heparin or aninhibitor of the anticoagulation effect of heparin. Said anticancerpharmaceutical compound may, for example, be one used in the art totreat the cancer that the subject has or has been diagnosed with.

The inhibitor of the anti-coagulation of heparin in embodiments of thepresent invention may be any of the anti-heparin compounds of U.S. Pub.No. 2011/0178104 A1, such as those of Formulas I, Ia, Ia-1, Ia-2, Ia-3,II, IIa, III, IV, or V, or pharmaceutically acceptable salts thereof.

The inhibitor of the anticoagulation effect of heparin may, for example,be a compound of any one of Formulas I, II, IIa, III, IV or V, or apharmaceutically acceptable salt thereof, as set forth below.

The inhibitor of the anticoagulation effect of heparin may, for example,be a compound of Formula I or a pharmaceutically acceptable saltthereof:R¹—[—X-A₁-Y—X-A₂-Y]_(m)—R²  Ior pharmaceutically acceptable salt thereof, wherein:

-   -   each X is, independently, NR⁸;    -   each Y is C═O;    -   each R⁸ is, independently, hydrogen or alkyl;    -   each A₂ is optionally substituted arylene or optionally        substituted heteroarylene, and    -   each A₁ is —(CH₂)q-, wherein q is 1 to 7, wherein A₁ and A₂ are        each, independently, optionally substituted with one or more PL        group(s), one or more NPL group(s), or a combination of one or        more PL group(s) and one or more NPL group(s);    -   R¹ is hydrogen, a PL group, or an NPL group, and R² is        —X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PL group, or an NPL        group; or    -   R¹ and R² are each, independently, hydrogen, a PL group, or an        NPL group; or    -   R¹ and R² together are a single bond; or    -   R¹ is —Y-A₂-X—R¹², wherein R¹² is hydrogen, a PL group, or an        NPL group, and R² is hydrogen, a PL group, or an NPL group;    -   each NPL group is, independently, —B(OR⁴)₂ or        —(NR3′)_(q1NPL)-U^(NPL)-LK^(NPL)-(NR^(3″))_(q2NPL)—R4′, wherein:    -   R³, R³′, and R^(3″) are each, independently, hydrogen, alkyl, or        alkoxy;    -   R⁴ and R⁴′ are each, independently, hydrogen, alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the        alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is        optionally substituted with one or more substituents, wherein        each substituent is, independently, alkyl, halo, or haloalkyl;    -   each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)2,        NR³, —C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—,        —N═N—NR³—, —C(═N—N(R³)2-), C(═NR³)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)20-, —S—C═N—, or —C(═O)—NR³—O—, wherein groups        with two chemically nonequivalent termini can adopt both        possible orientations;    -   each LK^(NPL) is, independently, —(CH₂)_(pNPL)— and C₂₋₈        alkenylenyl, wherein each of the (CH₂)_(pNPL) and C₂₋₈        alkenylenyl is optionally substituted with one or more        substituents, wherein each substituent is, independently, amino,        hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;    -   each pNPL is, independently, an integer from zero to 8;    -   q1NPL and q2NPL are each, independently, zero, 1, or 2;    -   each PL group is, independently, halo, hydroxyethoxymethyl,        methoxyethoxymethyl, polyoxyethylene, or        —(NR⁵′)_(q1PL)—U^(PL)-LK^(PL)-(NR⁵″)_(q2PL)—V, wherein:    -   R⁵, R⁵′, and R⁵″ are each, independently, hydrogen, alkyl, or        alkoxy; each U^(PL) is, independently, absent or O, S, S(═O),        S(═O)₂, NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—,        —C(═O)—NR⁵—N═N—, —N═N—NR⁵—, —C(═N—N(R⁵)2)-, —C(═NR⁵)—, —C(═O)O—,        —C(═O)S—, —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—,        wherein groups with two chemically nonequivalent termini can        adopt either of the two possible orientations;    -   each V is, independently, nitro, cyano, amino, halo, hydroxy,        alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH2)_(p)NH₂        wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,        C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,        —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,        —NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl,        cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each of the        aryl and cycloalkyl is substituted with one or more        substituents, wherein each of the heterocycloalkyl and        heteroaryl is optionally substituted with one or more        substituents, and wherein each of the subsituents for the aryl,        cycloalkyl, heterocycloalkyl, and heteroaryl is, independently,        nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio,        alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,        —NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone,        aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or        benzyloxycarbonyl;    -   each R^(e) is, independently, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,        or heterocycloalkylalkyl, each optionally substituted by one or        more substituents, wherein each substituent is, independently,        OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;    -   R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,        cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,        cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of the        C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        heteroaryl, cycloalkyl, heterocycloalkyl, aryl alkyl, heteroaryl        alkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally        substituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or        heterocycloalkyl;    -   or R^(d) and R^(e) together with the N atom to which they are        attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;    -   each LK^(PL) is, independently, —(CH₂)_(pPL) or C₂₋₈        alkenylenyl, wherein each of the —(CH₂)_(pPL)— and C₂₋₈        alkenylenyl is optionally substituted with one or more        substituents, wherein each substituent is, independently, amino,        hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;    -   each pPL is, independently, an integer from zero to 8;    -   q1PL and q2PL are each, independently, zero, 1, or 2;    -   m is an integer from 1 to about 20; and    -   at least one of A₁ is a —(CH₂)_(q)— group substituted with one        substituent, wherein the substituent is (CH₂)—V¹, (CH₂)₂—V¹,        —(CH₂)₃—V¹, —(CH₂)₄—V¹, or —(CH₂)₅—V¹, wherein V¹ is indolyl.

The inhibitor of the anti-coagulation activity of heparin may, forexample, be a compound of Formula I or a pharmaceutically acceptablesalt thereof, further in which:

-   -   each X is NH;    -   each A₂ is, independently, phenyl optionally substituted with        one or more substituents, wherein each substituent is,        independently, O—(CH₃), halo, or O—(CH₂)₂—V;    -   each A₁ is, independently, a —(CH₂)— group optionally        substituted with one substituent, wherein the substituent is        CH₃, —(CH₂)—V, —(CH₂)₂—V, —(CH₂)₃—V, —(CH₂)₄—V, or —(CH₂)₅—V;    -   each V is, independently, hydroxyl, amino, heteroarylamino,        ureido, guanidino, carbamoyl, C(═O)OH, —C(═O)OR^(c),        —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,        aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,        morpholino, azepanyl, azocanyl, tetrazolyl, 1,2,4-oxadiazolyl,        1,3,4-oxadiazolyl, imidazolyl, pyridinyl, indolyl, or a        substituted phenyl, wherein the substituted phenyl is        substituted with one or more substituents, wherein each        substituent is, independently, OH or amino; and    -   at least one of A₁ is a —(CH₂)— group substituted with one        substituent, wherein the substituent is (CH₂)—V¹, (CH₂)₂—V¹,        —(CH₂)₃—V¹, —(CH₂)₄—V¹, or —(CH₂)₅—V¹, wherein V¹ is indolyl.

The heparin binding compound of Formula I may be a heparin bindingcompound of Formula Ia as follows:

or a pharmaceutically-acceptable salt thereof, wherein

R¹ is hydrogen, an amino acid connected by its carbonyl group,—C(═NR³)—NR^(3″)R^(4′), —C(═O)—(CH₂)_(pNPL)—R^(4′),—C(═O)—(CH₂)_(pPL1)—V, —C(═O)-A₂-NH—C(═O)—(CH₂)_(pPL1)V, or—C(═O)-A₂-NH—C(═O)—(CH₂)_(pNPL)—R^(4′);

R³ and R^(3″) are each, independently, hydrogen, alkyl, or alkoxy;

R^(4′) is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, orheteroaryl, each of which is optionally substituted with one or moresubstituents, wherein each substituent is, independently, alkyl, halo,or haloalkyl;

each pNPL is, independently, an integer from 0 to 8;

pPL1 is an integer from 1 to 5; and

A₂ is optionally substituted arylene or optionally substitutedheteroarylene, wherein A₂ is optionally substituted with one or more PLgroups, one or more NPL groups, or a combination of one or more PLgroups and one or more NPL groups;

R² is OH, OR⁶⁰⁰, NH₂, NHR⁶⁰⁰, N(R⁶⁰⁰)₂, an amino acid connected by itsamino group, an α amino acid amide connected by its α amino group,—NH—(CH₂)_(pPL2)—V, or —NH-A₁-C(═O)—NH₂;

each R⁶⁰⁰ is, independently, unsubstituted alkyl or aryl, or eitheralkyl or aryl substituted with OH, halo, cyan, nitro, amino, alkoxy,alkylthio, alkylamino, or dialkylamino;

pPL2 is an integer from 1 to 5; and

A₁ is optionally substituted arylene or optionally substitutedheteroarylene, wherein A₁ is optionally substituted with one or more PLgroups, one or more NPL groups, or a combination of one or more PLgroups and one or more NPL groups;

each R⁹ is, independently, H, a PL group, or an NPL group;

each R¹⁰ is, independently, H, a PL group, or an NPL group;

or R⁹ and R¹⁰, taken together, constitute the side chain of a D or L αamino acid;

each R^(11a) is, independently, a PL group or an NPL group;

each NPL group is, independently, —B(OR⁴⁰)₂ or—(NR³)_(q1NPL)—U^(NPL)-LK^(NPL)-(NR^(3″))_(q2NPL)—R^(40′);

R^(3′) is hydrogen, alkyl, or alkoxy;

R⁴⁰ and R^(40′) are each, independently, hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, alkyl, halo, or haloalkyl;

each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂, NR³,—(C═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,—C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR³—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations;

each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or C₂₋₈alkenylenyl,wherein each of the (CH₂)_(pNPL) and C₂₋₈alkenylenyl is optionallysubstituted with one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

q1NPL and q2NPL are each, independently, 0, 1, or 2;

each PL group is, independently, halo, hydroxyethoxymethyl,methoxyethoxymethyl, polyoxyethylene, or—(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)-(NR^(5″))_(q2PL)—V, wherein:

R^(5′) and R^(5″) are each, independently, hydrogen, alkyl, or alkoxy;

each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂, NR⁵,—C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—,—C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt either of the two possible orientations;

each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1to 5, —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,—S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substituents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl;

each R^(c) is, independently, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆alkenyl,C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, eachoptionally substituted by one or more subsitutents, wherein eachsubstituent is, independently, OH, amino, halo, C₁₋₆ alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl,or heterocycloalkyl;

R^(d) and R^(e) are, independently, H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, orheterocycloalkylalkyl, wherein each of the C₁₋₆alkyl, C₁₋₆ haloalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl andheterocycloalkylalkyl is optionally substituted by OH, amino, halo,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl, or heterocycloalkyl;

or R^(d) and R^(e) together with the N atom to which they are attachedform a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;

each LK^(PL) is, independently—(CH₂)_(pPL3)— or C₂₋₈alkenylenyl, whereineach of the —(CH₂)_(pPL3)— or C₂₋₈alkenylenyl is optionally substitutedwith one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;

each pPL3 is, independently, an integer from 0 to 8;

q1PL and q2PL are each, independently, 0, 1, or 2;

each t1 is, independently, 0, 1, or 2; and

m is an integer from 1 to 20.

In some embodiments of the compound of Formula Ia or pharmaceuticallyacceptable salt thereof, the compound is a compound of Formula Ia-1,Ia-2, or Ia-3:

or a pharmaceutically acceptable salt thereof, wherein each R″ is,independently, H, alkyl, haloalkyl, or —(CH2)ppL-V, wherein pPL is aninteger from 1 to 5.

In some embodiments of the compound of Formula Ia-2 or Ia-3, orpharmaceutically acceptable salt thereof, each R″ is, independently,alkyl. In some embodiments, each R¹¹ is methyl.

In another embodiment, the inhibitor of the anti-coagulation activity ofheparin of Formula Ia is a compound having Formula Ia-4, as follows:

or a pharmaceutically acceptable salt thereof.

The inhibitor of the anti-coagulation activity of heparin may, forexample, be a compound of Formula II or a pharmaceutically acceptablesalt thereof, as follows:R¹—[—X-A₁-X—Y-A₂-Y—]_(m)—R²  IIor pharmaceutically acceptable salt thereof, wherein:

-   -   each X is, independently, NR⁸, O, S, —N(R⁸)N(R⁸)—,        —N(R⁸)—(N═N)—, —(N═N)—N(R⁸)—, —C(R⁷R⁷′)NR⁸—, —C(R⁷R⁷′)O—, or        —C(R⁷R⁷′)S—;    -   each Y is, independently, C═O, C═S, O═S═O, —C(═O)C(═O)—,        C(R⁶R⁶′)C═O, or C(R⁶R⁶′)C═S;    -   each R⁸ is, independently, hydrogen or alkyl;    -   each R⁷ and each R⁷′ are, independently, hydrogen or alkyl; or        R⁷ and R^(7′) together form —(CH₂)_(p)—, wherein p is 4 to 8;    -   each R⁶ and each R^(6′) are, independently, hydrogen or alkyl;        or R⁶ and R⁶′ together form —(CH₂)₂NR¹²(CH₂)₂—, wherein R¹² is        hydrogen, —C(═N)CH₃, or —C(═NH)—NH₂;    -   A₁ and A₂ are each, independently, optionally substituted        arylene or optionally substituted heteroarylene, wherein A₁ and        A₂ are each, independently, optionally substituted with one or        more PL group(s), one or more NPL group(s), or a combination of        one or more PL group(s) and one or more NPL group(s);    -   or each A₂ is, independently, optionally substituted arylene or        optionally substituted heteroarylene, and each A₁ is,        independently, optionally substituted C3 to C8 cycloalkyl,        wherein A₁ and A₂ are each, independently, optionally        substituted with one or more PL group(s), one or more NPL        group(s), or a combination of one or more PL group(s) and one or        more NPL group(s);    -   R¹ is hydrogen, a PL group, or an NPL group, and R² is        —X-A₁-X—R¹, wherein A₁ is as defined above and is optionally        substituted with one or more PL group(s), one or more NPL        group(s), or a combination of one or more PL group(s) and one or        more NPL group(s); or    -   R¹ is hydrogen, a PL group, or an NPL group, and R² is        —X-A′-X—R¹, wherein A′ is C₃ to C₈ cycloalkyl, aryl, or        heteroaryl and is optionally substituted with one or more PL        group(s), one or more NPL group(s), or a combination of one or        more PL group(s) and one or more NPL group(s); or    -   R¹ is —Y-A₂-Y—R², and R² is each, independently, hydrogen, a PL        group, or an NPL group; or    -   R¹ is —Y-A′ and R² is —X-A′, wherein each A′ is independently C₃        to C₈ cycloalkyl, aryl, or heteroaryl, and is optionally        substituted with one or more PL group(s), one or more NPL        group(s), or a combination of one or more PL group(s) and one or        more NPL group(s); or    -   R¹ and R² are, independently, a PL group, or an NPL group; or    -   R¹ and R² together form a single bond;    -   each NPL is, independently, —B(OR⁴)₂ or        —(NR^(3′))q1_(NPL)-U^(NPL)-LK^(NPL)-(NR^(3″))_(q2NPL)—R4′,        wherein:    -   R³, R³′, and R³″ are each, independently, hydrogen, alkyl, or        alkoxy;    -   R⁴ and R⁴′ are each, independently, hydrogen, alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the        alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is        optionally substituted with one or more alkyl or halo groups;    -   each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂,        NR³, —C(═O)—, C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—,        —N═N—NR³—, —C(═N—N(R³)₂)—, C(═NR³)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—, wherein groups        with two chemically nonequivalent termini can adopt both        possible orientations;    -   each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or        C₂₋₈alkenylenyl, wherein each of the (CH₂)_(pNPL)— and        C₂₋₈alkenylenyl is optionally substituted with one or more        substituents, wherein each substituent is, independently, amino,        hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;    -   each pNPL is, independently, an integer from zero to 8;    -   q1NPL and q2NPL are each, independently, zero, 1, or 2;    -   each PL is, independently, halo, hydroxyethoxymethyl,        methoxyethoxymethyl, polyoxyethylene, or        —(NR⁵′)_(q1PL)—U^(PL)-LK^(PL)-(NR⁵′)_(q2pL)—V, wherein:    -   R⁵, R⁵′, and R^(5″) are each, independently, hydrogen, alkyl, or        alkoxy;    -   each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂,        NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,        —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, C(═NR⁵)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups        with two chemically nonequivalent termini can adopt both        possible orientations;    -   each V is, independently, nitro, cyano, amino, hydroxy, alkoxy,        alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p        is 1 to 5, C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,        —N(CH₂CH₂NH2)₂, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,        —NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl,        cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each of the        aryl and cycloalkyl is substituted with one or more        substituents, wherein each of the heterocycloalkyl, and        heteroaryl is optionally substituted with one or more        substituents, and wherein each of the subsituents for the aryl,        cycloalkyl, heterocycloalkyl, and heteroaryl is, independently,        nitro, cyano, amino, hydroxy, alkoxy, alkylthio, alkylamino,        dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,        —NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone,        aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or        benzyloxycarbonyl;    -   each LK^(PL) is, independently, —(CH2)_(pPL) or C₂₋₈alkenylenyl,        wherein each of the —(CH₂)_(pPL) and C₂₋₈alkenylenyl is        optionally substituted with one or more substituents, wherein    -   each substituent is, independently, amino, hydroxyl, aminoalkyl,        hydroxylalkyl, or alkyl;    -   each pPL is, independently, an integer from zero to 8;    -   q1PL and q2PL are each, independently, zero, 1, or 2; and    -   m is an integer from 1 to about 20.

The compound of Formula II, or pharmaceutically salt thereof, may be acompound of Formula IIa, or a pharmaceutically acceptable salt thereof,as follows:R¹—X-A₁-X—Y-A₂-Y—X-A₁-X—R²  IIaor a pharmaceutically acceptable salt thereof, wherein:

-   -   each X is, independently, NR⁸, O, S, or —N(R⁸)N(R⁸)—;    -   each Y is, independently, C═O, C═S, or O═S═O;    -   each R⁸ is, independently, hydrogen or alkyl;    -   A₁ and A₂ are each, independently, optionally substituted        arylene or optionally substituted heteroarylene, wherein A₁ and        A₂ are each, independently, optionally substituted with one or        more PL group(s), one or more NPL group(s), or a combination of        one or more PL group(s) and one or more NPL group(s);    -   R¹ is a PL group or an NPL group;    -   R² is R¹ or the same as R¹;    -   each NPL is        —(NR³′)_(q1NP)—U^(NPL)-LK^(NPL)-(NR^(3″))_(q2NPL)—R⁴′, wherein:    -   R³, R³′, and R³″ are each, independently, hydrogen, alkyl, or        alkoxy;    -   R⁴ and R⁴′ are each, independently, hydrogen, alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the        alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is        optionally substituted with one or more alkyl or halo groups;    -   U^(NPL) is independently, absent or O, S, S(═O), S(═O)₂, NR³,        —C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—,        —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR³—O—, wherein groups        with two chemically nonequivalent termini can adopt either of        the two possible orientations;    -   each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or        C₂₋₈alkenylenyl, wherein the —(CH₂)_(pNPL)— is optionally        substituted with one or more substituents, wherein each        substituent is, independently, amino, hydroxyl, or alkyl;    -   each pNPL is, independently, an integer from zero to 8;    -   q1NPL and q2NPL are each, independently, zero, 1, or 2;    -   each PL is, independently, halo, hydroxyethoxymethyl,        methoxyethoxymethyl, polyoxyethylene, or        —(NR⁵′)_(q1PL)—U^(PL)-LK^(PL)-(NR⁵′)_(q2pL)—V, wherein:    -   R⁵, R⁵′, and R⁵″ are each, independently, hydrogen, alkyl, or        alkoxy;    -   each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂,        NR⁵, —C(═O)—, —C(O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,        —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)₂O—, —R⁵O—, —R⁵S—, —S—C═N—, or —C(═O)—NR⁵—O—,        wherein groups with two chemically nonequivalent termini can        adopt both possible orientations;    -   each V is, independently, nitro, cyano, amino, hydroxy, alkoxy,        alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p        is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,        —N(CH₂CH₂NF12)2, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,        —NH—S(═O)₂OH, S(═O)2OH, NR^(d)R^(e), semicarbazone, aryl,        heterocycloalkyl, or heteroaryl, wherein the aryl is substituted        with one or more substituents, wherein each of the        heterocycloalkyl and heteroaryl is optionally substituted with        one or more substituents, and wherein each of each of the        subsituents for the aryl, heterocycloalkyl, and heteroaryl is,        independently, nitro, cyano, amino, hydroxy, alkoxy, alkylthio,        alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(O)NH—OH, —O—NH—C(═NH)NH₂,        NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone,        aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or        benzyloxycarbonyl;    -   each LK^(PL) is, independently, —(CH₂)_(pPL)— or        C₂₋₈alkenylenyl, wherein the —(CH₂)_(pNPL)— is optionally        substituted with one or more substituents, wherein each        substituent is, independently, amino, hydroxyl, or alkyl;    -   each pPL is, independently, an integer from zero to 8; and    -   q1PL and q2PL are each, independently, zero, 1, or 2.

The inhibitor of the anticoagulation activity of heparin may, forexample, be a compound of Formula III or a pharmaceutically acceptablesalt thereof, as follows:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   each X is, independently, NR⁸;    -   each Y is C═O;    -   each R⁸ is, independently, hydrogen or alkyl;    -   each A₂ is optionally substituted arylene or optionally        substituted heteroarylene, and    -   each A₁ is —(CH₂)_(q)—, wherein q is 1 to 7, wherein A₁ and A₂        are each, independently, optionally substituted with one or more        PL group(s), one or more NPL group(s), or a combination of one        or more PL group(s) and one or more NPL group(s);    -   R² and R^(2a) are each, independently, hydrogen, a PL group, an        NPL group, or X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PL group,        or an NPL group;    -   L¹ is C₁₋₁₀ alkylene optionally substituted with one or more        substituents, wherein each substituent is, independently, alkyl,        halo, haloalkyl, aminoalkyl, hydroxylalkyl, V, or —(CH2)_(pPL)-V        wherein pPL is an integer from 1 to 5;    -   each NPL group is, independently, —B(OR⁴)₂ or        —(NR3′)_(q1NPL)-U^(NPL)-LK^(NPL)-(NR³″)_(q2NPL)—R⁴′, wherein:        -   R³, R³′, and R³″ are each, independently, hydrogen, alkyl,            or alkoxy;        -   R⁴ and R⁴′ are each, independently, hydrogen, alkyl,            alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl, wherein            each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or            heteroaryl is optionally substituted with one or more            substituents, wherein each substituent is, independently,            alkyl, halo, or haloalkyl;    -   each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂,        NR³, —C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—,        —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)₂O—, —S—CN—, or —C(═O)—NR³—O—, wherein groups        with two chemically nonequivalent termini can adopt both        possible orientations;    -   each LK^(NPL) is, independently, —(CH₂)_(pNPL) or        C₂₋₈alkenylenyl, wherein each of the —(CH₂)_(pNPL) and        C₂₋₈alkenylenyl is optionally substituted with one or more        substituents, wherein each substituent is, independently, amino,        hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;    -   each pNPL is, independently, an integer from zero to 8;    -   q1NPL and q2NPL are each, independently, zero, 1, or 2;    -   each PL group is, independently, halo, hydroxyethoxymethyl,        methoxyethoxymethyl, polyoxyethylene, or        —(NR⁵′)_(q1NPL)—U^(PL)-LK^(PL)-(NR⁵″)_(q2PL)—V, wherein:    -   R⁵, R⁵′, and R⁵″ are each, independently, hydrogen, alkyl, or        alkoxy;    -   each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂,        NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,        —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups        with two chemically nonequivalent termini can adopt either of        the two possible orientations;    -   each V is, independently, nitro, cyano, amino, halo, hydroxy,        alkoxy, alkylthio, alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂        wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═O)NH2 wherein p is 1 to 5, —NHC(═O)-alkyl,        —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,        —NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl,        cycloalkyl, heterocycloalkyl, or heteroaryl, wherein each of the        aryl and cycloalkyl is substituted with one or more        substituents, wherein each of the heterocycloalkyl and        heteroaryl is optionally substituted with one or more        substituents, and wherein each of the subsituents for the aryl,        cycloalkyl, heterocycloalkyl, and heteroaryl is, independently,        nitro, cyano, amino, halo, hydroxy, alkoxy, alkylthio,        alkylamino, dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido,        carbamoyl, —C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂,        —NH—S(═O)₂OH, S(═O)₂OH, NR^(d)R^(e), semicarbazone,        aminosulfonyl, aminoalkoxy, aminoalkythio, lower acylamino, or        benzyloxycarbonyl;    -   each R^(e) is, independently, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,        or heterocycloalkylalkyl, each optionally substituted by one or        more subsitutents, wherein each substituent is, independently,        OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;    -   R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl,        C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl,        cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,        cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of the        C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,        heteroaryl, cycloalkyl, heterocycloalkyl, aryl alkyl, heteroaryl        alkyl, cycloalkylalkyl and heterocycloalkylalkyl is optionally        substituted by OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,        aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or        heterocycloalkyl;        -   or R^(d) and R^(e) together with the N atom to which they            are attached form a 4-, 5-, 6-, 7-, or 8-membered            heterocycloalkyl;    -   each LK^(PL) is, independently, —(CH₂)_(pPL)— or        C₂₋₈alkenylenyl, wherein each of the ⁻(CH₂)pPL- and        C₂₋₈alkenylenyl is optionally substituted with one or more        substituents, wherein each substituent is, independently, amino,        hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;        -   each pPL is, independently, an integer from zero to 8        -   q1PL and q2PL are each, independently, zero, 1, or 2;        -   m11 is an integer from 1 to about 20; and        -   m12 is an integer from 1 to about 20.

The inhibitor of the anti-coagulation activity of heparin may, forexample, be a compound of Formula III, or a pharmaceutically acceptablethereof, further in which: each moiety of —[—X-A₁-Y—X-A₂-Y—]— is,independently, a moiety of:

-   -   each R⁹ is, independently, H, a PL group, or an NPL group;    -   each R^(m) is, independently, H, a PL group, or an NPL group;    -   each R^(11a) is, independently, a PL group or an NPL group; and    -   each t1 is independently zero, 1, or 2.

The inhibitor of the anti-coagulation activity of heparin may, forexample, be a compound of Formula IV, or a pharmaceutically acceptablesalt thereof, as follows:R¹—[X-A₁-Y—X-A₂-Y]_(m13)—X-L¹-Y—[—X-A₁-Y—X-A₂-Y—]_(m14)—R²  IVor a pharmaceutically acceptable salt thereof, wherein:

-   -   each X is, independently, NR⁸;    -   each Y is C═O;    -   each R⁸ is, independently, hydrogen or alkyl;    -   each A₂ is optionally substituted arylene or optionally        substituted heteroarylene, and each A₁ is —(CH₂)_(q)—, wherein q        is 1 to 7, wherein A₁ and A₂ are each, independently, optionally        substituted with one or more PL group(s), one or more NPL        group(s), or a combination of one or more PL group(s) and one or        more NPL group(s);    -   R¹ is hydrogen, a PL group, or an NPL group, and R² is        —X-A₁-Y—R¹¹, wherein R¹¹ is hydrogen, a PL group, or an NPL        group; or    -   R¹ and R² are each, independently, hydrogen, a PL group, or an        NPL group; or    -   R¹ and R² together are a single bond; or    -   R¹ is —Y-A₂-X—R¹², wherein R¹² is hydrogen, a PL group, or an        NPL group, and R² is hydrogen, a PL group, or an NPL group;    -   L¹ is C₁₋₁₀ alkylene optionally substituted with one or more        substituents, wherein each substituent is, independently, alkyl,        halo, haloalkyl; aminoalkyl, hydroxylalkyl, V, or (CH₂)_(pPL)—V        wherein pPL is an integer from 1 to 5;    -   each V is, independently, hydroxy, amino, alkylamino,        dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,        —N(CH₂CH₂NH₂)₂, guanidino, amidino, ureido, carbamoyl, —C(═O)OH,        —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(O)₂OH,        S(═O)₂OH, NR^(d)R^(e), a substituted aryl group,        heterocycloalkyl, or heteroaryl, wherein each of the        heterocycloalkyl and heteroaryl is optionally substituted with        one more substituents, wherein each substituent is,        independently, amino, halo, cyano, nitro, hydroxy,        —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂, amidino,        guanidino, aminosulfonyl, aminoalkoxy, aminoalkythio, lower        acylamino, or benzyloxycarbonyl; and wherein the substituted        aryl group is substituted with one more substituents, wherein        each substituent is, independently, amino, halo, cyano, nitro,        hydroxy, —NH(CH2)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,        amidino, guanidino, aminosulfonyl, aminoalkoxy, aminoalkythio,        lower acylamino, or benzyloxycarbonyl;    -   each NPL group is, independently, —B(OR⁴)₂ or        —(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)-(NR^(3″))_(q2NPL)—R⁴′,        wherein:    -   R³, R³′, and R³″ are each, independently, hydrogen, alkyl, or        alkoxy;    -   R⁴ and R^(4′) are each, independently, hydrogen, alkyl, alkenyl,        alkynyl, cycloalkyl, aryl, or heteroaryl, wherein each of the        alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heteroaryl is        optionally substituted with one or more substituents, wherein        each substituent is, independently, alkyl, halo, or haloalkyl;    -   each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)2,        NR³, —C(═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—,        —N═N—NR³—, —C(═N—N(R³)₂)—, —C(═NR)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)2O—, —S—C═N—, or —C(═O)—NR³—O—, wherein groups        with two chemically nonequivalent termini can adopt both        possible orientations;    -   each LK^(NPL) is, independently, —(CH₂)_(pNPL)— or        C₂₋₈alkenylenyl, wherein each of the —(CH₂)pNPL— or        C₂₋₈alkenylenyl is optionally substituted with one or more        substituents, wherein each substituent is, independently, amino,        hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;    -   each pNPL is, independently, an integer from zero to 8;    -   q1NPL and q2NPL are each, independently, zero, 1, or 2;    -   each PL group is, independently, halo, hydroxyethoxymethyl,        methoxyethoxymethyl, polyoxyethylene, or        —(NR⁵′)_(q1PL)—U^(PL)-LK^(PL)-(NR⁵″)q2pL-V, wherein:    -   R⁵, R⁵′, and R⁵″ are each, independently, hydrogen, alkyl, or        alkoxy;    -   each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂,        NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—,        —N═N—NR⁵—, —C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—,        —C(═S)—, —O—P(═O)₂O—, —S—C═N—, or —C(═O)—NR⁵—O—, wherein groups        with two chemically nonequivalent termini can adopt either of        the two possible orientations;    -   each R^(e) is, independently, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,        heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl,        or heterocycloalkylalkyl, each optionally substituted by one or        more subsitutents, wherein each substituent is, independently,        OH, amino, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;    -   R^(d) and R^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, heteroaryl,        cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,        cycloalkylalkyl, or heterocycloalkylalkyl, wherein each of the        C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,        heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,        heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl is        optionally substituted by OH, amino, halo, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, cycloalkyl, or heterocycloalkyl;    -   or R^(d) and R^(e) together with the N atom to which they are        attached form a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;    -   each LK^(PL) is, independently, —(CH₂)_(pPL)— or        C₂₋₈alkenylenyl, wherein each of the —(CH2)_(pPL)— and        C₂₋₈alkenylenyl is optionally substituted with one or more        substituents, wherein each substituent is, independently, amino,        hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;    -   each pPL is, independently, an integer from zero to 8;    -   q1PL and q2PL are each, independently, zero, 1, or 2;    -   m13 is an integer from 1 to about 10; and    -   m14 is an integer from 1 to about 10.

The inhibitor of the anti-coagulation effect of heparin may, forexample, be a compound of Formula IV, or pharmaceutically acceptablesalt thereof, further in which:

-   -   each moiety of —[—X-A₁-Y—X-A₂-Y—]— is, independently, a moiety        of:

-   -   each R⁹ is, independently, H, a PL group, or an NPL group;    -   each R¹⁰ is, independently, H, a PL group, or an NPL group;    -   each R^(11a) is, independently, a PL group or an NPL group; and    -   each t1 is independently zero, 1, or 2.

The inhibitor of the anti-coagulation activity of heparin may, forexample, be a compound of Formula V or a pharmaceutically acceptablesalt thereof, as follows:R¹—[—X-A¹-X—Y-A²-Y—]_(m)—R²  Vor a pharmaceutically acceptable salt thereof, wherein:

-   -   each of the moiety of —X-A¹-X— is, independently, a moiety of        Formula XXI-1, XXI-2, XXI-3, XXI-4, XXI-5, XXI-6, XXI-7, or        XXI-8:

-   -   where Het is any 5 or 6-member ring heterocycle;    -   each of the moiety of —Y-A²-Y— is, independently, a moiety of        Formula XXII-1, XXII-2, XXII-3, XXII-4, or XXII-5:

-   -   R¹ is hydrogen, —C(═O)R¹¹, or —Y-A²-Y—R¹²;    -   R² is —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)2, —NH—C(NH)NH₂,        —NH(CH₂)_(p)NH₂ wherein p is an integer from 1 to 5,        —NH(CH₂)_(p)NH(C₁₋₄ alkyl) wherein p is an integer from 1 to 5,        —NH(CH₂)_(p)N(C₁₋₄ alkyl)₂ wherein p is an integer from 1 to 5,        —NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is an integer from 1 to 5,        R^(12a), or —X-A¹-X—R¹³;    -   each R¹⁰ is, independently, —C(═O)NH₂, —C(═O)NH(CH₂)_(p)NH₂        wherein p is an integer from 1 to 5, —C(═O)NH(CH2)_(p)NH(C₁₋₄        alkyl) wherein p is an integer from 1 to 5,        —C(═O)NH(CH₂)_(p)N(C₁₋₄ alkyl)₂ wherein p is an integer from 1        to 5, —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is an integer from        1 to 5, —OCH₃, or —R^(10a);    -   each R^(10a) is, independently, C₁₋₈ alkyl substituted with        R^(A);    -   each R^(A) is independently —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄        alkyl)₂, —NH—C(NH)NH₂, —C(═O)NH₂, or —C(═O)OH;    -   each R¹¹ is, independently, C₁₋₈ alkyl or aryl, each substituted        with 0, 1, 2, or 3 substituents each independently selected from        —OCH₃, —OR^(11a), —C(═O)NH₂, —C(═O)NH(CH₂)_(p)NH₂ wherein p is        an integer from 1 to 5, —C(═O)NH(CH₂)_(p)NH(C₁₋₄alkyl) wherein p        is an integer from 1 to 5, —C(═O)NH(CH2)_(p)N(C₁₋₄alkyl)₂        wherein p is an integer 20 from 1 to 5,        —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is an integer from 1 to        5, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, or —NH—C(═NH)NH₂;    -   each R^(11a) is, independently, C₁₋₈ alkyl substituted with        R^(B);    -   each R^(B) is, independently, —NH2, —NH(C₁₋₄ alkyl), —N(C₁₋₄        alkyl)₂, —NH—C(═NH)NH₂, or —C(═O)NH₂;    -   R¹² is —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,        —NH—C(NH)NH₂, —NH(CH₂)_(p)NH₂ wherein p is an integer from 1 to        5, —NH(CH₂)_(p)NH(C₁₋₄alkyl) wherein p is an integer from 1 to        5, —NH(CH₂)_(p)N(C₁₋₄ alkyl)₂ wherein p is an integer from 1 to        5, —NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is an integer from 1 to 5,        or R^(12a);    -   R^(12a) is a moiety of Formula XXXI:

-   -   R¹³ is hydrogen or —C(═O)R¹¹    -   t1 is zero, 1, or 2; and    -   m is 1, 2, 3, or 4, provided that:

(a) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXI-4;

(b) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXI-5;

(c) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least two different moieties of Formulas XXI-1,XXI-2, XXI-3, XXI-4, or XXI-5;

(d) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXI-4 and at least onemoiety of Formula XXI-1, XX1-2, XX1-3, or XX1-5;

(e) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXI-5 and at least onemoiety of Formula XXI-1, XXI-3, or XXI-4;

(f) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXII-2;

(g) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXII-3;

(h) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXII-2 and at leastone moiety of Formula XXII-1, XXII-3, or XXII-4;

(i) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXII-3 and at leastone moiety of Formula XXII-1, XXII-2, or XXII-4;

(j) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least two different moieties of Formulas XXII-1,XXII-2, XXII-3 and XXII-4;

(k) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXXI;

(l) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least two different moieties of Formula XXI-6,XXI-7, or XXI-8;

(m) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXI-6 and at least onemoiety of Formula XXI-7 or XXI-8;

(n) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXI-7 and at least onemoiety of Formula XXI-8;

(o) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXII-5;

(p) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXII-5 and at leastone moiety of Formula XXII-1, XXII-3, or XXII-4;

(q) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least two different moieties of Formulas XXII-1,XXII-2, XXII-3, XXII-4, and XXII-5; or

(r) the compound of Formula V, or pharmaceutically acceptable saltthereof, comprises at least one moiety of Formula XXXI, or a compoundselected from Compound Nos. 201-427 of U.S. Pub. No. 2011/0178104 A1.

The inhibitor of the anti-coagulation activity of heparin may, forexample, be a compound of Formula V, or pharmaceutically acceptable saltthereof, further in which the moiety of Formula XXII-1 is a moiety ofXXII-1-a or XXII-1-b:

Methods for making compounds of Formulas I, II, IIa, III, IV or V areknown in the art and disclosed in U.S. Pub. No. 2011/0178104 A1, U.S.Pub. No. 2006/0041023 A1, U.S. Pat. No. 7,173,102, and InternationalPub. No. WO2005/123660.

The inhibitor of the anticoagulation activity of heparin may, forexample, be a compound or salt that binds to heparin with an EC₅₀ ofless than about 100, 90, 80, 70, 60, 50, 40, 30, 20, 15, 10, 5, 2, 1,0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06,0.05, 0.02, 0.01, 0.001, 0.0001, or 0.00001 μg/mL. The inhibitor of theanticoagulation activity of heparin may, for example, be compound orsalt that binds to heparin with an EC₅₀ less than about 30, 20, 15, 10,5, 2, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, 0.001,0.0001, or 0.00001 μg/mL.

It has been reported that tetra-[5-(L)-lysyl-amino-O-methylsalicylamide]in a clinical study for the reversal of heparin anticoagulation therapycaused an undesirable decrease in blood pressure at the doses used.Tetra-[5-(L)-lysyl-amino-O-methylsalicylamide] is reported to bindheparin tightly and essentially irreversibly under physiologicalconditions. Advantageously, in the present invention,tetra-[5-(L)-lysyl-amino-O-methylsalicylamide] in a prebound-to-heparinform may be used for administration to the subject, which is believed tobe free of the blood pressure decrease phenomena. Furtheradvantageously, while heparin reversal in the context of anticoagulationtherapy is often an acute situation in which slow administration is anunacceptable option for reducing side effects, in the present inventionwhich is directed to the inhibition of metastasis, slow/sloweradministration (than used for acute reversal of heparin anticoagulation)is a valid option for reducing or eliminating side effects otherwiseseen with acute administration of an inhibitor of the anticoagulationactivity of heparin.

While vitamin K is not believed to be a direct inhibitor of theanticoagulation activity of heparin, it may nevertheless be used in anyof the aforementioned embodiments, in combination with heparin, since itacts to compensate deficiencies in coagulation that may be subclinicalor not clinically relevant outside the context of the administration ofheparin but potentially deleterious during the administration of theheparin. In this regard, the co-administration of vitamin K at least inpart counterbalances the anticoagulation effect of the heparin on asystemic level. Vitamin K may, for example, be used in addition to aninhibitor of the anticoagulation effect of heparin as described herein.

Vitamin K may, for example, be administered in a dose of 0.25-10.0 mg.This dose may be optionally repeated as needed, for example, every 2, 3,4, 5, 6, or 7 days during the course of co-treatment with the heparin.Vitamin K may, for example, be administered orally, subcutaneously,intramuscularly or intravenously. Vitamin K used may, for example, beVitamin K₁ or Vitamin K₂ or any mixture thereof. Synthetic forms ofVitamin K, such as K₃, K₄ and K₅ may also be employed.

As used herein, the terms “comprising” (and any form of comprising, suchas “comprise”, “comprises”, and “comprised”), “having” (and any form ofhaving, such as “have” and “has”), “including” (and any form ofincluding, such as “includes” and “include”), or “containing” (and anyform of containing, such as “contains” and “contain”), are inclusive oropen-ended and do not exclude additional, un-recited elements or methodsteps. However, wherever such open-ended language is recited herein, itis also meant to not only encompass but to also disclose thecorresponding, more limited situations typically expressed as“consisting essentially of” and closed-ended language “consisting of.”

As used herein, the terms “a” or “an” means “at least one” or “one ormore” unless the context clearly indicates otherwise. However, whereverthe term “a” or “an” is recited herein, it is also meant to not onlyencompass but to also disclose the corresponding, more limited instanceof only one thing.

As used herein, the term “about” means that the numerical value isapproximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical limitation isused, unless indicated otherwise by the context, “about” means thenumerical value can vary by +10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “n-membered”, where n is an integer, typicallydescribes the number of ring-forming atoms in a moiety, where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiophene is an example of a 5-memberedheteroaryl ring.

As used herein, the term “alkyl” refers to a saturated hydrocarbon groupwhich is straight-chained or branched. An alkyl group can contain from 1to 20, from 2 to 20, from 1 to 10, from 1 to 8, from 1 to 6, from 1 to4, or from 1 to 3 carbon atoms. Examples of alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like.

As used herein, the term “alkylene” or “alkylenyl” refers to a divalentalkyl linking group. An example of an alkylene (or alkylenyl) ismethylene or methylenyl (i.e., —CH₂—).

As used herein, the term “alkenyl” refers to an alkyl group having oneor more double carbon-carbon bonds. Examples of alkenyl groups include,but are not limited to, ethenyl, propenyl, cyclohexenyl, and the like.

As used herein, the term “alkenylenyl” refers to a divalent linkingalkenyl group.

As used herein, the term “alkynyl” refers to an alkyl group having oneor more triple carbon-carbon bonds. Examples of alkynyl groups include,but are not limited to, ethynyl, propynyl, and the like.

As used herein, the term “alkynylenyl” refers to a divalent linkingalkynyl group.

As used herein, the term “haloalkyl” refers to an alkyl group having oneor more halogen substituents. Examples of haloalkyl groups include, butare not limited to, CF₃, C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅, CH₂CF₃, and thelike.

As used herein, the term “aryl” refers to monocyclic or polycyclic(e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons. In someembodiments, aryl groups have from 6 to about 20 carbon atoms. In someembodiments, aryl groups have from 6 to 10 carbon atoms. Examples ofaryl groups include, but are not limited to, phenyl, naphthyl,anthracenyl, phenanthrenyl, indanyl, indenyl, and the like.

As used herein, the term “cycloalkyl” refers to non-aromatic cyclichydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups thatcontain up to 20 ring-forming carbon atoms. Cycloalkyl groups caninclude mono- or polycyclic ring systems such as fused ring systems,bridged ring systems, and spiro ring systems. In some embodiments,polycyclic ring systems include 2, 3, or 4 fused rings. A cycloalkylgroup can contain from 3 to about 15, from 3 to 10, from 3 to 8, from 3to 6, from 4 to 6, from 3 to 5, or from 5 to 6 ring-forming carbonatoms. Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and thelike. Also included in the definition of cycloalkyl are moieties thathave one or more aromatic rings fused (i.e., having a bond in commonwith) to the cycloalkyl ring, for example, benzo or thienyl derivativesof pentane, pentene, hexane, and the like (e.g.,2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl).

As used herein, the term “heteroaryl” refers to an aromatic heterocyclehaving up to 20 ring-forming atoms and having at least one heteroatomring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. Insome embodiments, the heteroaryl group has at least one or moreheteroatom ring-forming atoms, each of which are, independently, sulfur,oxygen, or nitrogen. In some embodiments, the heteroaryl group has from1 to about 20 carbon atoms, from 1 to 5, from 1 to 4, from 1 to 3, orfrom 1 to 2, carbon atoms as ring-forming atoms. In some embodiments,the heteroaryl group contains 3 to 14, 3 to 7, or 5 to 6 ring-formingatoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or1 to 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic(e.g., having 2, 3 or 4 fused rings) systems. Examples of heteroarylgroups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrryl, oxazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and thelike.

As used herein, the term “heterocycloalkyl” refers to non-aromaticheterocycles having up to 20 ring-forming atoms including cyclizedalkyl, alkenyl, and alkynyl groups, where one or more of thering-forming carbon atoms is replaced by a heteroatom such as an O, N,or S atom. Heterocycloalkyl groups can be mono or polycyclic (e.g.,fused, bridged, or spiro systems). In some embodiments, theheterocycloalkyl group has from 1 to about 20 carbon atoms, or 3 toabout 20 carbon atoms. In some embodiments, the heterocycloalkyl groupcontains 3 to 14, 3 to 7, or 5 to 6 ring-forming atoms. In someembodiments, the heterocycloalkyl group has 1 to 4, 1 to 3, or 1 to 2heteroatoms. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 triple bonds. Example of heterocycloalkyl groupsinclude, but are not limited to, morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, andthe like. In addition, ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally substituted by oxo or sulfido.For example, a ring-forming S atom can be substituted by 1 or 2 oxo(i.e., form a S(O) or S(O)₂). For another example, a ring-forming C atomcan be substituted by oxo (i.e., form carbonyl). Also included in thedefinition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring including, but not limited to, pyridinyl,thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives ofheterocycles such as indolene, isoindolene, isoindolin-1-one-3-yl,4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl, and3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by oxo or sulfido.

As used herein, the term “halo” refers to halogen groups including, butnot limited to fluoro, chloro, bromo, and iodo.

As used herein, the term “alkoxy” refers to an —O-alkyl group. Examplesof alkoxy groups include, but are not limited to, methoxy, ethoxy,propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

As used herein, the term “haloalkoxy” refers to an —O-haloalkyl group.An example of an haloalkoxy group is OCF₃.

As used herein, the term “alkylthio” refers to an —S-alkyl group. Anexample of an alkylthio group is —SCH₂CH₃.

As used herein, the term “arylalkyl” refers to a C₁-6 alkyl substitutedby aryl and “cycloalkylalkyl” refers to C₁-6 alkyl substituted bycycloalkyl.

As used herein, the term “heteroarylalkyl” refers to a C₁-6 alkyl groupsubstituted by a heteroaryl group, and “heterocycloalkylalkyl” refers toa C₁-6 alkyl substituted by heterocycloalkyl.

As used herein, the term “amino” refers to NH₂.

As used herein, the term “alkylamino” refers to an amino groupsubstituted by an alkyl group. An example of an alkylamino is —NHCH₂CH₃.

As used herein, the term “arylamino” refers to an amino groupsubstituted by an aryl group. An example of an alkylamino is—NH(phenyl).

As used herein, the term “aminoalkyl” refers to an alkyl groupsubstituted by an amino group. An example of an aminoalkyl is—CH₂CH₂NH₂.

As used herein, the term “aminosulfonyl” refers to —S(═O)₂NH₂.

As used herein, the term “aminoalkoxy” refers to an alkoxy groupsubstituted by an amino group. An example of an aminoalkoxy is—OCH₂CH₂NH₂.

As used herein, the term “aminoalkylthio” refers to an alkylthio groupsubstituted by an amino group. An example of an aminoalkylthio is—SCH₂CH₂NH₂.

As used herein, the term “amidino” refers to —C(═NH)NH₂.

As used herein, the term “acylamino” refers to an amino groupsubstituted by an acyl group (e.g., —O—C(═O)—H or —O—C(═O)-alkyl). Anexample of an acylamino is —NHC(═O)H or —NHC(═O)CH₃. The term “loweracylamino” refers to an amino group substituted by a loweracyl group(e.g., —O—C(═O)—H or —O—C(═O)—C₁-6alkyl). An example of a loweracylamino is —NHC(═O)H or —NHC(═O)CH₃.

As used herein, the term “carbamoyl” refers to —C(═O)—NH₂.

As used herein, the term “cyano” refers to —CN.

As used herein, the term “dialkylamino” refers to an amino groupsubstituted by two alkyl groups.

As used herein, the term “diazamino” refers to —N(NH₂)₂.

As used herein, the term “guanidino” refers to —NH(═NH)NH₂.

As used herein, the term “heteroarylamino” refers to an amino groupsubstituted by a heteroaryl group. An example of an alkylamino is—NH-(2-pyridyl).

As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” refers to analkyl group substituted by a hydroxyl group. Examples of a hydroxylalkylinclude, but are not limited to, —CH₂OH and —CH₂CH₂OH.

As used herein, the term “nitro” refers to —NO₂.

As used herein, the term “semicarbazone” refers to ═NNHC(═O)NH₂.

As used herein, the term “ureido” refers to —NHC(═O)—NH₂.

As used herein, the phrase “optionally substituted” means thatsubstitution is optional and therefore includes both unsubstituted andsubstituted atoms and moieties. A “substituted” atom or moiety indicatesthat any hydrogen on the designated atom or moiety can be replaced witha selection from the indicated substituent group, provided that thenormal valency of the designated atom or moiety is not exceeded, andthat the substitution results in a stable compound. For example, if amethyl group is optionally substituted, then 3 hydrogen atoms on thecarbon atom may be replaced with substituent groups.

As used herein, the term, “compound” refers to all stereoisomers,tautomers, and isotopes of the compound described.

As used herein, the phrase “substantially isolated” refers to a compoundthat is at least partially or substantially separated from theenvironment in which it is formed or detected.

As used herein, the phrase “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of humans and animals, such as those known in the art.

As used herein, the term “subject” or “patient,” used interchangeably,refers to any mammal, such as mice, rats, other rodents, rabbits, dogs,cats, swine, cattle, sheep, horses, or primates, such as humans.

Heparin used according to the invention may, for example, beunfractionated heparin or a low molecular weight heparin such asTinzaparin, Reviparin, or Enoxaparin. Unfractionated heparin may, forexample, be administered to achieve a plasma concentration of 0.05 to1.0 units/mL, for example, 0.2 to 0.4 units/mL. The heparin may, forexample, be dosed with an IV bolus dose of 5,000 to 10,000 units ofheparin, followed by an infusion of 1,000 units per hour. The units arecalculated in the same manner as if the heparin were to be used foranticoagulation even though the anticoagulation activity will beinhibited. In an alternative example, a loading dose of 50-100 units/kgof heparin followed by a constant infusion of 15-25 units/kg/hr may beused. Therapeutic levels for patients treated with heparin for venousthromboembolism are around 1 anti-factor Xa unit/mL for low molecularweight heparins, typically measured at 3 to 4 hours after injection—forany heparins used according to the invention, a dosing providing thesame plasma concentration of anti-factor Xa units, as would be presentin the absence of inhibitors of heparin's anti-coagulation effect, maybe used. Larger or smaller doses may also be used.

Doses of heparins such as unfractionated heparins or low molecularweight heparins used may, for example, be in the range of 0.1 mg-200 mgper day, such as 1 mg-200 mg per day, such as 1 mg-100 mg/day, such as10 mg-100 mg per day, such as 20-80 mg, 30-70 mg or 30-60 mg per day.Dosing may continue, for example, for 2-7 days, for at least 7 days, forat least 10 days, for 10-14 days, for at least 14 days, for at least 20days, for at least one month, or for at least two months. Dosing may becontinuous and indefinite recognizing that there may be days that areskipped and/or that there may be on- and off-periods built into thedosing schedule. Continuous dosing is desirable to prevent an existingcancer susceptible to metastasis from spreading.

As described hereinabove, an amount of inhibitor of the anticoagulationeffect of heparin may be used that at least substantially inhibits theanticoagulation activity of the amount of heparin used. For anyparticular heparin and such inhibitor, the relative amount of inhibitorto heparin required for complete or partial inhibition of theanticoagulation activity of the heparin may be determined empiricallyusing anticoagulation assays such as those routine methods known in theart. For inhibitors of the anticoagulation activity of heparin that bindheparin, the relative amount of inhibitor to maximally “bind-up” theheparin can be routinely determined by titrating the binding to heparin(mixing known amounts of inhibitor and heparin under binding conditionsand determining how much inhibitor remains unbound at differentamounts). Heparin binding assays are well known in the art anddisclosed, for example, in U.S. Pub. No. 2011/0178104 A1. For inhibitorsof the anticoagulation activity of heparin that bind heparin,pharmaceutical compositions of the inhibitor bound to the heparin may,for example, be prepared by mixing an excess of the inhibitor with aquantity of the heparin under binding conditions and thereafterremoving, for example by filtering, the unbound inhibitor from themixture, prior to the administration to a patient.

While not wishing to be limited by any particular theory of mechanism,it is believed that heparins inhibit metastasis at least in part bymodulating the interaction of otherwise metastasizing cells withselectins, particularly, P-selectin and L-selectin. The anti-metastaticmoieties of heparin are distinct and/or separable from theanti-coagulant moieties. Anticoagulant activity of a heparin preparationcan be depleted by passing the heparin through an antithrombin column.The heparin eluent maintains anti-metastatic activity but notsubstantial anti-coagulant activity. However, it is believed that themajority of the anti-metastatic heparin also has antithrombin bindingsites and remains on the column. In contrast, the present invention cantake advantage of essentially the entire anti-metastatic potential in aheparin population of glycosaminoglycans.

Each of the patents, patent applications or other publications citedherein is hereby incorporated by reference as if fully set forth in itsentirety. Although the invention has been described in connection withvarious embodiments, it should be understood that the invention asclaimed should not be unduly limited to such specific embodiments.

What is claimed is:
 1. A method for preparing a pharmaceuticalcomposition for the inhibition of metastasis in a mammal comprising thesteps of: mixing in water or an aqueous solution an anti-metastaticheparin preparation having anti-coagulant activity in the absence of aninhibitor thereof, and an inhibitor of the anti-coagulation activity ofheparin that binds heparin or a pharmaceutically-acceptable saltthereof, to obtain a solution in which at least some of the inhibitor ofthe anti-coagulation activity of heparin that binds heparin is bound tothe anti-metastatic heparin preparation; and removing said inhibitorthat remains unbound to the anti-metastatic heparin preparation from theanti-metastatic heparin preparation after the mixing step, wherein theinhibitor of the anti-coagulation activity of heparin that binds heparincomprises a compound having the formula:

or a pharmaceutically-acceptable salt thereof, wherein R¹ is hydrogen,an amino acid connected by its carbonyl group, —C(═NR³)—NR^(3″)R^(4′),—C(═O)—(CH₂)_(pNPL)—R^(4′), —C(═O)—(CH₂)_(pPL1)—V,—C(═O)-A₂-NH—C(═O)—(CH₂)_(pPL1)—V, or—C(═O)-A₂-NH—C(═O)—(CH₂)_(pNPL)—R^(4′); R³ and R^(3″) are each,independently, hydrogen, alkyl, or alkoxy; R^(4′) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl, each of which isoptionally substituted with one or more substituents, wherein eachsubstituent is, independently, alkyl, halo, or haloalkyl; each pNPL is,independently, an integer from 0 to 8; pPL1 is an integer from 1 to 5;and A₂ is optionally substituted arylene or optionally substitutedheteroarylene, wherein A₂ is optionally substituted with one or more PLgroups, one or more NPL groups, or a combination of one or more PLgroups and one or more NPL groups; R² is OH, OR⁶⁰⁰, NH₂, NHR⁶⁰⁰,N(R⁶⁰⁰)₂, an amino acid connected by its amino group, an α amino acidamide connected by its α amino group, —NH—(CH₂)_(pPL2)—V, or—NH-A₁-C(═O)—NH₂; each R⁶⁰⁰ is, independently, unsubstituted alkyl oraryl, or either alkyl or aryl substituted with OH, halo, cyan, nitro,amino, alkoxy, alkylthio, alkylamino, or dialkylamino; pPL2 is aninteger from 1 to 5; and A₁ is optionally substituted arylene oroptionally substituted heteroarylene, wherein A₁ is optionallysubstituted with one or more PL groups, one or more NPL groups, or acombination of one or more PL groups and one or more NPL groups; each R⁹is, independently, H, a PL group, or an NPL group; each R¹⁰ is,independently, H, a PL group, or an NPL group; or R⁹ and R¹⁰, takentogether, constitute the side chain of a D or L α amino acid; eachR^(11a) is, independently, a PL group or an NPL group; each NPL groupis, independently, —B(OR⁴⁰)₂ or—(NR^(3′))_(q1NPL)—U^(NPL)-LK^(NPL)-(NR^(3″))_(q2NPL)—R^(40′); R^(3′) ishydrogen, alkyl, or alkoxy; R⁴⁰ and R^(40′) are each, independently,hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or heteroaryl,wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, andheteroaryl is optionally substituted with one or more substituents,wherein each substituent is, independently, alkyl, halo, or haloalkyl;each U^(NPL) is, independently, absent or O, S, S(═O), S(═O)₂, NR³,—(C═O)—, —C(═O)—NR³—, —C(═O)—N═N—NR³—, —C(═O)—NR³—N═N—, —N═N—NR³—,—C(═N—N(R³)₂)—, —C(═NR³)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR³—O—, wherein groups with two chemicallynonequivalent termini can adopt both possible orientations; eachLK^(NPL) is, independently, —(CH₂)_(pNPL)— or C₂₋₈ alkenylenyl, whereineach of the (CH₂)_(pNPL) and C₂₋₈ alkenylenyl is optionally substitutedwith one or more substituents, wherein each substituent is,independently, amino, hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl;q1NPL and q2NPL are each, independently, 0, 1, or 2; each PL group is,independently, halo, hydroxyethoxymethyl, methoxyethoxymethyl,polyoxyethylene, or —(NR^(5′))_(q1PL)—U^(PL)-LK^(PL)-(NR^(5″))_(q2PL)—V,wherein: R^(5′) and R^(5″) are each, independently, hydrogen, alkyl, oralkoxy; each U^(PL) is, independently, absent or O, S, S(═O), S(═O)₂,NR⁵, —C(═O)—, —C(═O)—NR⁵—, —C(═O)—N═N—NR⁵—, —C(═O)—NR⁵—N═N—, —N═N—NR⁵—,—C(═N—N(R⁵)₂)—, —C(═NR⁵)—, —C(═O)O—, —C(═O)S—, —C(═S)—, —O—P(═O)₂O—,—S—C═N—, or —C(═O)—NR⁵—O—, wherein groups with two chemicallynonequivalent termini can adopt either of the two possible orientations;each V is, independently, nitro, cyano, amino, halo, hydroxy, alkoxy,alkylthio, alkylamino, dialkylamino, amido, alkylamido, dialkylamido,—NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —C(═O)NH(CH₂)_(p)NH₂ wherein p is 1to 5, —C(═O)NH(CH₂)_(p)NHC(═NH)NH₂ wherein p is 1 to 5,—C(═O)NH(CH₂)_(p)NHC(═O)NH₂ wherein p is 1 to 5, —NHC(═O)-alkyl,—N(CH₂CH₂NH₂)₂, diazamino, amidino, guanidino, ureido, carbamoyl,—C(═O)OH, —C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH,—S(═O)₂OH, NR^(d)R^(e), semicarbazone, aryl, cycloalkyl,heterocycloalkyl, or heteroaryl, wherein each of the aryl and cycloalkylis substituted with one or more substituents, wherein each of theheterocycloalkyl and heteroaryl is optionally substituted with one ormore substituents, and wherein each of the substituents for the aryl,cycloalkyl, heterocycloalkyl, and heteroaryl is, independently, nitro,cyano, amino, halo, hydroxy, alkoxy, alkylthio, alkylamino,dialkylamino, —NH(CH₂)_(p)NH₂ wherein p is 1 to 5, —N(CH₂CH₂NH₂)₂,diazamino, amidino, guanidino, ureido, carbamoyl, —C(═O)OH,—C(═O)OR^(c), —C(═O)NH—OH, —O—NH—C(═NH)NH₂, —NH—S(═O)₂OH, S(═O)₂OH,NR^(d)R^(e), semicarbazone, aminosulfonyl, aminoalkoxy, aminoalkythio,lower acylamino, or benzyloxycarbonyl; each R^(c) is, independently,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl, each optionally substitutedby one or more subsitutents, wherein each substituent is, independently,OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl; R^(d) andR^(e) are, independently, H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl, wherein eachof the C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl and heterocycloalkylalkyl is optionally substituted byOH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;or R^(d) and R^(e) together with the N atom to which they are attachedform a 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl; each LK^(PL) is,independently —(CH₂)_(pPL3)— or C₂₋₈ alkenylenyl, wherein each of the—(CH₂)_(pPL3)— or C₂₋₈ alkenylenyl is optionally substituted with one ormore substituents, wherein each substituent is, independently, amino,hydroxyl, aminoalkyl, hydroxylalkyl, or alkyl; each pPL3 is,independently, an integer from 0 to 8; q1PL and q2PL are each,independently, 0, 1, or 2; each t1 is, independently, 0, 1, or 2; and mis an integer from 1 to 20, and wherein the compound or pharmaceuticallyacceptable salt thereof binds the antithrombin III binding site ofheparin.
 2. The method of claim 1, wherein in the mixing step, thequantity of the inhibitor of the anti-coagulation activity of heparinthat binds heparin or a pharmaceutically-acceptable salt thereof isprovided in excess of the anti-thrombin III binding sites present in theanti-metastatic heparin preparation having anti-coagulant activity inthe absence of an inhibitor thereof that is provided.
 3. The method ofclaim 1, wherein m is an integer from 3 to
 6. 4. The method of claim 1,further comprising the step of: after the removing step, drying theanti-metastatic heparin preparation to obtain a dry anti-metastaticheparin preparation to which at least some of the inhibitor of theanti-coagulation activity of heparin that binds heparin is bound.
 5. Themethod of claim 1, wherein the inhibitor of the anti-coagulationactivity of heparin that binds heparin comprises a compound having theformula:

or a pharmaceutically acceptable salt thereof.
 6. The method of claim 5,wherein m is an integer from 3 to
 6. 7. The method of claim 5, furthercomprising the step of: after the removing step, drying theanti-metastatic heparin preparation to obtain a dry anti-metastaticheparin preparation to which at least some of the inhibitor of theanti-coagulation activity of heparin that binds heparin is bound.
 8. Themethod of claim 5, wherein the inhibitor of the anti-coagulationactivity of heparin that binds heparin comprises a compound having theformula:

or a pharmaceutically acceptable salt thereof.
 9. The method of claim 8,further comprising the step of: after the removing step, drying theanti-metastatic heparin preparation to obtain a dry anti-metastaticheparin preparation to which at least some of the inhibitor of theanti-coagulation activity of heparin that binds heparin is bound.